Intraarterial stents have become the primary therapy for treating coronary artery disease because they limit the elastic recoil and late vascular wall remodeling following angioplasty. Restenosis, in this case, is an iatrogenic complication of the additional arterial injury caused by stent placement itself, and evolves as a process by which vascular smooth muscle cells abnormally migrate and proliferate into the lumen of an artery following stent placement, causing obstruction to normal blood flow. Restenosis rates for patients undergoing stent placement procedures remain unacceptably high, resulting in clinical failure in up to 20-30% (and in some series, up to 40%) of patients by 6-9 months. Thus, the anticipated clinical impact of drug-coated stents that would prevent these cellular responses leading to restenosis and clinical failure is very significant. Based on our previous research which demonstrated that the anti-tumor drug, paclitaxel (Taxol), might have clinical promise to prevent vascular restenosis ,we examined whether paclitaxel-coated coronary stents would be effective at preventing neointimal proliferation in a porcine model of restenosis. We found that paclitaxel-coated coronary stents produced a significant dose-dependent inhibition of neointimal hyperplasia and luminal encroachment in the pig LAD coronary artery 28 days after implantation, without any significant complications (i.e., no aneurysm, thrombosis, or death) The long-term studies (6-9 month outcomes) are currently in progress and continue to show that the entire range of doses tested is safe. The dose-efficacy assessment is still in progress. From these latest studies it is now becoming clear that there is the early restoration of several critical aspects of normal vascular architecture and health, including complete regrowth and relining of the artery by endothelial cells (a major positive anatomic and clinical benchmark of vascular healing) at paclitaxel doses that are emerging from these studies as likely to be the most efficacious. The development of restenosis at the site of prior coronary stenting, called "in-stent" restenosis, is also a significant clinical problem. In collaboration with Johns Hopkins University, we have begun testing paclitaxel in a pig model of in-stent restenosis in which two stents are deployed in the left anterior descending (LAD) coronary artery at the same location one month apart. The first stent, a 3 mm x 9 mm un-coated NIR stent, was deployed in the LAD to produce arterial injury and induce neointima formation. The second stent, a 3 mm x 16 mm paclitaxel-coated (60 ug/stent) or uncoated NIR stent, was deployed inside of the original stent 30 days later. One month after the second stent, the pigs were sacrificed and the presence of neointimal hyperplasia at the injury site analyzed using angiographic and histological methods. Preliminary results show that neointima formation one month after placement of the second stent was similar in the paclitaxel-treated and control groups. In contrast, the arterial lumen in the drug-treated animals was almost 40% larger than in the untreated controls, consistent with presence of positive arterial remodeling. These effects were confirmed in the post-mortem angiographic results, which showed a larger dye-filled arterial lumen in the pigs receiving a second stent coated with paclitaxel (vs the uncoated stent group). These results suggest that local delivery of paclitaxel is therapeutically effective in relieving coronary obstruction resulting from in-stent restenosis. Based on our studies, leading to years of preclinical and clinical development in multiple academic centers workdwide, a paclitaxel-eluting coronary stent system has been implemented by Boston Scientific and granted FDA approval (March 2004) for clinical use in the United States. It is estimated that the paclitaxel stent share of the U.S. drug-eluting stent market is in excess of 65-70%. Preliminary worldwide monthly sales of the paclitaxel-eluting coronary stent system (August 2004) were approximately $200 million.